AIDS vaccine developments.
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AIDS Vaccines↗
Biomedical subjects
D Dormont
Publications and source records attributed to D Dormont.
Specific and non-specific immunity and protection of macaques against SIV infection.
The simian immunodeficiency virus is a retrovirus closely related to the human immunodeficiency viruses; it induces an AIDS-like disease in macaques, and provides therefore an obvious animal model for anti-lentiviral drug and vaccine strategy assessments. In our experiment, we immunized rhesus macaques with a purified and formalin-inactivated whole SIVmac251 antigen preparation. Most of these monkeys were still protected for more than 4 months following a heterologous SIVsm intravenous challenge. Both virus stocks, for vaccine preparation and challenge, were provided by culture supernatants of infected T cells of human origin. Four of the protected macaques were then reimmunized with the same antigen preparation and rechallenged intravenously with a homologous rhesus cell grown SIVmac251. Unexpectedly, all animals developed clinical and biological evidence of infection by day 15 after the second challenge.
Animals↗
Functional consequences of monocyte/macrophage infection by HIV1.
Monocyte/macrophage infection by human immunodeficiency virus type 1 (HIV1) was studied for its effects on the production of tumour necrosis factor alpha (TNF alpha) and the expression of the manganese superoxide dismutase (MnSOD) gene. For this purpose, human peripheral blood monocytes were obtained from healthy HIV1-seronegative donors by centrifugal elutriation and infected with either the HIV1/LAV1 strain or with the primary HIV1/DAS isolate. The results showed that (1) HIV1/LAV1-infected macrophages did not produce any biologically detectable TNF alpha during the few hours following lentiviral infection, despite rises in the TNF alpha mRNA level; (2) MnSOD gene transcription in the macrophages increased, as measured 2 and 4 h after infection; (3) the level of the MnSOD gene expression declined during the late phases of lentiviral infection, but TNF alpha synthesis and gene expression rose; and (4) bispecific antibody comprised of anti-Fc gamma RI (anti-CD64) and anti-gp41 monoclonal antibodies inhibited the in vitro infection of monocyte-derived macrophages by HIV1/DAS.
Antigens, Differentiation↗
Identification of a neutralizing domain in the external envelope glycoprotein of simian immunodeficiency virus.
Two murine monoclonal antibodies (MAbs), designated MATG2014 and MATG2033, were generated. They are reactive with the external envelope glycoprotein gp130 of the simian immunodeficiency virus of macaque monkey (SIVmac251), and display a cell-free virus neutralizing activity in vitro. In addition, MATG2014 cross-reacts with HIV-2Rod gp140. Epitope mapping of these MAbs was performed by screening and SIVmac peptide library expressed in yeast and confirmed using synthetic peptides. MATG2014 and MATG2033 recognize two overlapping epitopes localized in an 18 residue domain between amino acid 171 and 188 of the SIVmac251 gp130. Sera from experimentally SIV-infected macaques are immunoreactive with this neutralizing domain. Sequence comparison with related SIV and HIV-2 viral strains indicates a low variability of this region, consistent with the cross-reactivity of MATG2014 with HIV-2Rod gp140. This domain should then be considered in designing experimental vaccines.
Amino Acid Sequence↗
Bispecific antibody targeting of human immunodeficiency virus type 1 (HIV-1) glycoprotein 41 to human macrophages through the Fc IgG receptor I mediates neutralizing effects in HIV-1 infection.
Human monocyte-derived macrophages that express the CD4 molecule and the Fc receptor for IgG (Fc gamma R) play a major role in the pathogenesis of human immunodeficiency virus (HIV) infection. To explore this possibility further, human monoclonal antibody to glycoprotein 41 (gp41) was produced, and a heterobifunctional antibody composed of F(ab') x F(ab')2 fragments of monoclonal anti-gp41 and anti-Fc gamma RI 22.2 were constructed. Both antibodies were analyzed for neutralizing effects, and the role of the CD4 molecule in HIV infection was studied with human monocyte-derived macrophages. The bispecific antibody exhibited strong neutralizing properties, in contrast to the monoclonal anti-gp41 antibody. Moreover, in the presence of monoclonal anti-Leu-3a antibody, viral production was completely inhibited. These findings demonstrate the necessity of the CD4 molecule in HIV infection of human macrophages and emphasize the usefulness of such heterobifunctional antibody directed to virus and monocyte-derived macrophage Fc receptors in prevention of HIV infection.
Antibodies, Monoclonal↗
Variations in prion protein and glial fibrillary acidic protein mRNAs in the brain of scrapie-infected newborn mouse.
To begin to understand the molecular basis of cases of Creutzfeldt-Jakob disease recently described in young children, the expression of prion protein and glial fibrillary acidic protein (GFAP) mRNAs was investigated during the development of the brain of scrapie-infected newborn mice. Changes in the time course of expression were identified by Northern blot quantification between days 1 and 172. Although scrapie-infected and control animals showed no detectable changes in brain development (first 56 days of life), GFAP mRNAs were found to increase significantly as early as day 84. A 10-fold increase in the level of GFAP mRNA was observed in brain between day 112 and death (day 172).
Animals↗
Human immunodeficiency virus type 1 major neutralizing determinant exposed on hepatitis B surface antigen particles is highly immunogenic in primates.
Hepatitis B surface antigen (HBsAg) produced by recombinant DNA technology is now widely and safely used worldwide for hepatitis B vaccination. We used the HBsAg particle as a carrier molecule for presentation of selected human immunodeficiency virus type 1 (HIV-1) determinants to the immune system. Immunization of rhesus monkeys with an HBsAg chimera carrying the HIV-1 envelope major neutralizing determinant allowed us to generate proliferative T-cell responses and, in some cases, neutralizing antibodies and antibody-dependent cellular cytotoxicity. Since there is an overlap between populations at risk for hepatitis B virus and HIV, HBsAg recombinant particles may be relevant carriers for HIV-1 epitopes and could offer a new approach to the development of an AIDS vaccine.
Amino Acid Sequence↗
Differential human immunodeficiency virus expression in CD4+ cloned lymphocytes: from viral latency to replication.
By using cloning methodology, 13 CD4+, CD8-, CD45RO+, and CD29+ clones, isolated from human immunodeficiency virus (HIV)-negative donors, have been characterized and tested regarding their susceptibility to two strains of HIV type 1 (HIV-1). Infected clones possess integrated provirus. Only six are able to replicate HIV-1, while seven may normally grow without cytopathic effect and without viral replication. These results argue that all CD4+ lymphocyte clones may be infectable but that a heterogeneity exists regarding their abilities to replicate HIV-1.
Antigens, CD↗
Frequency of central lesions in polyneuropathy associated with IgM monoclonal gammopathy: an MRI, neurophysiological and immunochemical study.
CNS lesions were studied in polyneuropathy associated with IgM monoclonal gammopathy. Eleven out of 12 patients with IgM MGUS and one patient with Waldenstrom's disease had clinical and electrophysiological features indicating a demyelinating polyneuropathy. MRI showed CNS white matter lesions in two cases. Antibodies reacting against glycolipids present in CNS white matter were present in five cases, two of which had abnormal MRI. Central conduction times cortex-C7, obtained by magnetic stimulation, were prolonged in 3/8 patients, of which two patients had anti-CNS glycolipid antibodies.
Aged↗
[Creutzfeldt-Jakob disease in 4 children treated with growth hormone].
Creutzfeldt-Jakob disease was diagnosed in four growth hormone recipients at the age of 10, 11, 18 and 19 years. To our knowledge, the two first cases are the first instances of Creutzfeldt-Jakob disease recorded in children. Three of them were still being treated with synthetic hormone at the onset of the disease. Neurological disorders: ataxia and diplopia, appeared first, dementia and myoclonus appeared later. Eighteen cases of Creutzfeldt-Jakob disease in growth hormone recipients are now recorded, and the present risk of Creutzfeldt-Jakob disease in pituitary growth recipients is estimated to be 1/300. Because of the long incubation period, new cases are to be feared. Other causes of iatrogenic Creutzfeldt-Jakob disease are reviewed. These facts incite to consider carefully using products of human origin in human therapy. The interactions between growth hormone, prion and host's genomic make-up are still not clear.
Adolescent↗
MRI in neurosarcoidosis.
Nine patients with neurological manifestations of sarcoidosis were explored by MRI and, in some cases, CT. The MRI examinations were performed in T1- and T2-weighted spin-echo sequences in all patients, with gadolinium injection in seven. Several non-specific lesions were demonstrated, the most frequent of them showing on T2-weighted sequences as high-intensity signals in the periventricular white matter and the semi-oval centres. Other abnormalities, such as infiltrations of the hypothalamo-pituitary region, granulomatous masses within the brain tissue and meningeal infiltrations, were observed. These findings were in agreement with those found in the literature. Gadolinium injection seems to be important in this pathology, as it demonstrates lesions that are not visible on conventional T1- and T2-weighted spin-echo sequences.
Adult↗
Clinical and virological aspects of HIV2 infection in rhesus monkeys.
To establish an animal model of AIDS, two different "wild" or "adapted" HIV2 Rod and Eho strains were cultivated on monkey cells from different species (baboons, cynomolgus, Rhesus monkeys). Five different available strains were then injected both by intravenous (i.v.) and intracerebral (i.c.) route into ten Rhesus monkeys. Seven animals seroconverted between days 13 and 230. Reverse transcriptase activity in the lymphocyte culture supernatants was detectable in six of the seven animals that seroconverted, and in one animal that remained seronegative. Lymphopenia and a decrease in the CD4+ cell counts were observed in eight animals. One animal, inoculated with HIV2-Rod "wild type," developed a severe cachexia, with dyspnea, and associated neurological symptoms 150 days after inoculation. This animal was sacrificed on day 220. Pathological examination showed typical lesions of actinomycetes infection in the lungs and in the meninges. Another monkey had significant weight loss associated with lymphadenopathies and pancytopenia. These results suggest that in vivo replication of HIV2 in Rhesus monkeys may induce clinical symptoms of immune deficiency. This method is reproducible and may provide a good model for AIDS.
Animals↗
[Complications of intraperitoneal chemotherapy by the needle technique. Evaluation after ten years].
A hundred and twenty three patients with intraperitoneal cancer (mostly ovarian) were treated between 1980 and 1990 with intraperitoneal chemotherapy administered through a "needle". Local complications were infinitely fewer and less serious than those observed with materials implanted for months. General complications depended on which protocols were being used. But tolerance on the whole was better when the drugs were administered intraperitoneally. This is particularly clear with cisplatin, although the dose is doubled intraperitoneally over a period of 10 months instead of 6. In this ways there was hardly any neurotoxicity and there was a noteworthy prolongation of survival time in cases of ovarian carcinoma.
Antineoplastic Combined Chemotherapy Protocols↗
[Infective particles in non-conventional virus encephalitis. A mystery of modern biology].
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Encephalitis↗
[Ovarian carcinomas. Intraperitoneal chemotherapy by needle].
Between January 1980 and February 1988, 61 women with ordinary ovarian carcinoma (OC) were treated with combined intraperitoneal and intravenous first-line therapy. For intraperitoneal infusions we did not use implanted systems which are often poorly tolerated and sometimes create non-negligible complications. We simply used a lumbar puncture needle left in situ for less than 2 hours. In second regard laparotomies, the 7 patients with stage I OC and the 3 patients with stage II OC were in histologically and cytologically proven complete remission, as were 34 of the 43 patients with stage III OC (79 percent) and 1 of the 8 patients with stage IV OC. After a mean follow-up of 56 months, the overall actuarial survival rate was 66 percent and the survival rate without recurrence was 54 percent. During the same period, 26 patients with recurrent OC were treated with second-line intraperitoneal chemotherapy. After a mean follow-up of 30 months, 10 were in apparently complete remission, and after a 27 to 61 months period 7 of these 10 patients had no recurrence. These results must be compared with those obtained with other salvage methods.
Abdominal Pain↗
Neonatal diagnosis of HIV infection.
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Adult↗
Insulin increases the rate of degradation of 2-deoxy-glucose-6-phosphate in the perfused rat heart: a 31P NMR study.
The effect of insulin on the production and degradation of 2-deoxyglucose-6-phosphate (2DG6P) from 2-deoxyglucose (2DG) in the Langendorff-perfused rat heart was studied by 31P NMR. The 2DG concentrations ranged from 0.25 to 20 mM in the 5 mM acetate perfusion medium, and from 2 to 4 mM in the 12 mM glucose medium. With acetate as the carbon source, the apparent Km for the production of 2DG6P was 7 mM and Vmax was 1.8 mumols/min/mg prot. Insulin enhanced Vmax 7-fold without change in Km of the transporter. With glucose perfusion, insulin had no effect on the initial rate of production of 2DG6P. The interpretation is that glucose phosphorylation is regulated by work when glucose is the energy substrate. In acetate-perfused hearts, in the conditions where the 2DG6P content reached a plateau, the rate of production of 2DG6P (equal to the measured degradation rate, see below) was eight times smaller than the initial rate, both with and without insulin. In glucose-perfused hearts, it was the same as the initial rate. The degradation of 2DG6P upon interruption of 2DG perfusion was exponential. The time constant was the same in acetate or glucose. It was strongly affected by insulin, being 225 +/- 60 min without, and 92 +/- 13 min with insulin. The observation that 2DG6P degradation is sensitive to insulin in the heart shows that its rate may vary. This possibility should be kept in mind in the analysis of PET studies of glucose metabolism.
Acetates↗
Regulation of the glial fibrillary acidic protein, beta actin and prion protein mRNAs during brain development in mouse.
Developmental regulation in mRNAs of three brain proteins has been investigated by Northern blot evaluation in C57BL/6 mice. The mRNAs of two cytoskeletal components, glial fibrillary acidic protein (GFAP) and beta actin, varied significantly, and differently, during brain development (0-56 days postnatal). The beta actin mRNAs peaked at day 1 after a slight increase, then dropped rapidly during the first 15 days postnatal, and thereafter remained at a level which was strictly maintained throughout development and adulthood. Conversely, the GFAP mRNAs increased during the first two weeks after birth (astroglial proliferation), and then slightly declined until the adult stage (astroglial cell differentiation). The prion protein (PrP) mRNAs were detectable as soon as birth, and increased 4-fold during brain maturation. Then, during the adult life, the GFAP and PrP mRNAs did not change markedly. Nevertheless, slight but significant increases in the mRNA levels of both GFAP and PrP were observed at older stages (360 days). These results are analysed in the light of the implications of PrP and GFAP in scrapie infection models.
Actins↗